Mitochondrial Defects and Metabolic Vulnerabilities in Lynch Syndrome-Associated MSH2-Deficient Endometrial Cancer

Authors

Mikayla Borthwick Bowen
Brenda Melendez
Qian Zhang
Diana Moreno
Leah Peralta
Wai Kin Chan
Collene Jeter
Lin Tan
M Anna Zal
Philip L Lorenzi
Kenneth Dunner
Richard K Yang
Russell R Broaddus
Joseph Celestino
Nisha Gokul
Elizabeth Whitley
Deena M Scoville
Tae Hoon Kim
Jae-Wook Jeong
Rosemarie Schmandt
Karen Lu
Hyun-Eui Kim
Melinda S Yates

Publication Date

2-18-2025

Journal

JCI Insight

Abstract

Lynch syndrome (LS), caused by inherited mutations in DNA mismatch repair genes, including MSH2, carries a 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, mechanisms driving LS-associated EC (LS-EC) remain unclear. We investigated MSH2 loss in EC pathogenesis using a mouse model (PR-Cre Msh2LoxP/LoxP, abbreviated Msh2KO), primary cell lines, human tissues, and human EC cells with isogenic MSH2 knockdown. By 8 months, 58% of Msh2KO mice developed endometrial atypical hyperplasia (AH), a precancerous lesion. At 12-16 months, 50% of Msh2KO mice exhibited either AH or ECs with histologic similarities to human LS-ECs. Transcriptomic profiling of EC from Msh2KO mice revealed mitochondrial dysfunction-related pathway changes. Subsequent studies in vitro and in vivo revealed mitochondrial dysfunction based on 2 mechanisms: mitochondrial content reduction and structural disruptions in retained mitochondria. Human LS-ECs also exhibited mitochondrial content reduction compared with non-LS-ECs. Functional studies demonstrated metabolic reprogramming of MSH2-deficient EC, including reduced oxidative phosphorylation and increased susceptibility to glycolysis suppression. These findings identified mitochondrial dysfunction and metabolic disruption as consequences of MSH2 deficiency in EC. Mitochondrial and metabolic aberrations should be evaluated as biomarkers for endometrial carcinogenesis or risk stratification and represent potential targets for cancer interception in women with LS.

Keywords

Disease Models, Animal, Humans, Female, Animals, Mice, Middle Aged, Aged, Cell Line, Tumor, Endometrial Neoplasms, Colorectal Neoplasms, Hereditary Nonpolyposis, MutS Homolog 2 Protein, Metabolic Reprogramming, Mitochondrial Diseases, Mitochondrial Turnover

DOI

10.1172/jci.insight.185946

PMID

39964762

PMCID

PMC11949016

PubMedCentral® Posted Date

2-18-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes